Clinical Virology Laboratory, Innovative Biotech, Keffi/Abuja, Nigeria.
PLoS One. 2011;6(8):e23233. doi: 10.1371/journal.pone.0023233. Epub 2011 Aug 4.
Creation of an effective vaccine for HIV has been an elusive goal of the scientific community for almost 30 years. Neutralizing antibodies are assumed to be pivotal to the success of a prophylactic vaccine but previous attempts to make an immunogen capable of generating neutralizing antibodies to primary "street strain" isolates have resulted in responses of very limited breadth and potency. The objective of the study was to determine the breadth and strength of neutralizing antibodies against autologous and heterologous primary isolates in a cohort of HIV-1 infected Nigerians and to characterize envelopes from subjects with particularly broad or strong immune responses for possible use as vaccine candidates in regions predominated by HIV-1 CRF02_AG and G subtypes. Envelope vectors from a panel of primary Nigerian isolates were constructed and tested with plasma/sera from the same cohort using the PhenoSense HIV neutralizing antibody assay (Monogram Biosciences Inc, USA) to assess the breadth and potency of neutralizing antibodies. The immediate goal of this study was realized by the recognition of three broadly cross-neutralizing sera: (NG2-clade CRF02_AG, NG3-clade CRF02_AG and NG9- clade G). Based on these findings, envelope gp140 sequences from NG2 and NG9, complemented with a gag sequence (Clade G) and consensus tat (CRF02_AG and G) antigens have been codon-optimized, synthesized, cloned and evaluated in BALB/c mice. The intramuscular administration of these plasmid DNA constructs, followed by two booster DNA immunizations, induced substantial specific humoral response against all constructs and strong cellular responses against the gag and tat constructs. These preclinical findings provide a framework for the design of candidate vaccine for use in regions where the HIV-1 epidemic is driven by clades CRF02_AG and G.
近 30 年来，科学界一直致力于研发有效的 HIV 疫苗，但收效甚微。中和抗体被认为是预防性疫苗成功的关键，但之前尝试制造一种能够产生针对原始“街头株”分离物的中和抗体的免疫原，其结果仅产生了非常有限的广度和效力的中和抗体反应。本研究的目的是确定一组 HIV-1 感染的尼日利亚人中针对自体和异源原发性分离物的中和抗体的广度和效力，并对具有特别广泛或强大免疫反应的个体的包膜进行特征描述，以便在以 HIV-1 CRF02_AG 和 G 亚型为主的地区将其用作候选疫苗。构建了一组来自尼日利亚的原发性分离物的包膜载体，并使用来自同一队列的血浆/血清在 PhenoSense HIV 中和抗体测定法（Monogram Biosciences Inc，美国）中进行了测试，以评估中和抗体的广度和效力。这项研究的直接目标是通过识别三种广泛交叉中和的血清来实现：（NG2-分支 CRF02_AG、NG3-分支 CRF02_AG 和 NG9-分支 G）。基于这些发现，来自 NG2 和 NG9 的包膜 gp140 序列，与 gag 序列（分支 G）和共识 tat（CRF02_AG 和 G）抗原一起进行了密码子优化，并已合成、克隆和在 BALB/c 小鼠中进行了评估。这些质粒 DNA 构建体的肌肉内给药，随后进行两次增强 DNA 免疫接种，可诱导针对所有构建体的大量特异性体液反应，并针对 gag 和 tat 构建体产生强烈的细胞反应。这些临床前发现为在由 CRF02_AG 和 G 分支驱动的 HIV-1 流行地区使用候选疫苗的设计提供了框架。
